Patients with mutations in the β-subunit of the succinate dehydrogenase (SDHB) have the highest risk to develop metastatic phaeochromocytomas and paragangliomas (PPGLs). Progress in clinical therapy development is hindered by limited availability of suitable model systems.  We generated a sdhb^rmc200 zebrafish mutant and to be able to study the pathways behind tumorigenesis and identify and test new therapeutic targets in vivo. We discovered similar metabolic characteristics in the homozygous mutant larvae as observed in human SDHB-associated PPGLs. We also investigate the potential of the adult sdhb zebrafish as functional tumour model. To detect and monitor PPGL tumour development in adult zebrafish we use multiple functional read-outs: e.g. histology, functional imaging (MRI) and endocrine parameters.

So far, identical to the human situation, natural development of tumour formation has been very rarely observed in adult heterozygous sdhb mutants. Human heterozygous carriers of SDHB germline mutations requires a “second-hit” in which the wild-type allele is disabled in the tumour tissue. To mimic the human situation more closely, a tissue-specific mutant will be generated. Furthermore, to induce tumour formation and accelerate tumour growth we explore different aggravation strategies. As first strategy, to randomly induce a second hit radiation is applied in heterozygous adult sdhb mutant zebrafish. Second, adult zebrafish are housed in a hypoxic environment to stimulate HIF-1α stabilisation considered to be involved in tumorigenesis. Third, diet alterations as prooxidants are used to increase the level of reactive oxygen species (ROS) which is also hypothesized to be involved in PPGL tumorigenesis. Altogether, these aggravation strategies are being used to create a functional tumour model for SDHB-associated PPGLs in order to be able to study the pathways behind tumorigenesis and identify and test new therapeutic targets in vivo.